(2007) Hypertriglyceridemia: its etiology, effects and treatment. afpserv@aafp.org for copyright questions and/or permission requests. Hunninghake DB, Although remnant lipoproteins are generally cleared by hepatic uptake, they can also be taken up by the vascular endothelium where they promote inflammation and atherosclerosis by a variety of mechanisms including abnormal endothelial cell secretion and impaired flow mediated dilatation.151617 This would be especially relevant when generation of TGRL is increased and clearance is decreased in certain pathologic conditions as discussed below. 1975;231:360–81. Cleeman JI, Thompson PD, Copyright © 2007 by the American Academy of Family Physicians. The class I recommendation first identifies a population 20 years of age or older who have moderate hypertriglyceridemia defined as fasting or nonfasting triglycerides (TG) 175-499 mg/dL (1.9-5.6 mmol/L) and advises searching for and treating secondary factors (see Table 1). Fish oil contains high amounts of the essential fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA); these acids also are known as omega-3 fatty acids. The Food and Drug Administration (FDA) has granted Orphan Drug designation to ARO-APOC3 (Arrowhead Pharmaceuticals), an investigational treatment for familial chylomicronemia syndrome (FCS). However, these general recommendations need to be modified in patients with extreme hypertriglyceridemia due to FCS who need restriction of dietary fat to below 10-15% of total energy intake (15-20 g/day).126 Limited data also suggest a benefit of medium chain triglycerides in these patients, as they are absorbed and transported without being incorporated into chylomicrons.127128, Regular aerobic exercise not only promotes weight loss and physical fitness but has been shown to significantly reduce postprandial triglyceride response. 1996;3:213–9.... 2. et al. An omega-3 polyunsaturated fatty acid concentrate administered for one year decreased triglycerides in simvastatin treated patients with coronary heart disease and persisting hypertriglyceridemia. 30. Di Gregorio D, Khan MA, Robins SJ, Hypertriglyceridemia is a “risk enhancing factor” favoring statin treatment to reduce LDL cholesterol and thereby favorably affect risk of ASCVD. Lancet. Glass TR, Her clinical features are also suggestive of underlying familial combined hyperlipidemia (family history of hypercholesterolemia and CHD), and the recent marked elevation in serum triglycerides leading to pancreatitis is likely secondary to uncontrolled diabetes and oral estrogen therapy. As a result, the condition clusters in families. This is due to inhibition of statin glucoronidation by fibrates, especially gemfibrozil, which increases statin concentrations. Harrison RA, ROBERT C. OH, MPH, MAJ, MC, USA, Tripler Army Medical Center, Honolulu, Hawaii, J. BRIAN LANIER, CPT, MC, USA, Martin Army Community Hospital, Fort Benning, Georgia. et al. et al. Both agents are in phase 2-3 trials. Clofibrate and niacin in coronary heart disease. Please note: your email address is provided to the journal, which may use this information for marketing purposes. et al. LDL-C = low-density lipoprotein cholesterol; HDL-C = high-density lipoprotein cholesterol. Davidson MH. Alsheikh-Ali AA, On the basis of these observations, the manuscript was modified to include a discussion on novel therapies and an acknowledgment of the difficulties faced by patients with genetic hypertriglyceridemia, Series explanation: State of the Art Reviews are commissioned on the basis of their relevance to academics and specialists in the US and internationally. Appel LJ, The safety of rosuvastatin as used in common clinical practice: a postmarketing analysis. Franklin BA, Etiology and risk of lactescent plasma and severe hypertriglyceridemia. Recently, interest has been growing in novel therapies aimed at increasing lipoprotein lipase mediated clearance of TGRL by decreasing the activity of proteins that inhibit lipoprotein lipase such as apolipoprotein C-III and ANGPTL 3/4. Would genetic testing have any benefit? Her family history was significant for hypercholesterolemia and premature coronary artery disease but not for pancreatitis or severe hypertriglyceridemia. Cook TJ, This may be related to decreased biliary cholesterol concentration with statin treatment, whereas fibrates increase biliary cholesterol concentration and risk of gall stones.138139 However, the triglyceride lowering effect of fibrates in patients with severe hypertriglyceridemia is likely a bigger determinant of the risk of pancreatitis, justifying its use under these circumstances. Evidence supporting the different drug and non-drug approaches to treating hypertriglyceridemia is examined, and an easy to adopt step-by-step management strategy is presented. Betteridge J, : National Heart, Lung, and Blood Institute, 2002. This article exemplifies the AAFP 2007 Annual Clinical Focus on management of chronic illness. Familial hypertriglyceridemia is a genetic condition that causes the triglyceride levels in the blood to get too high. Berge KG, They note that patients with triglycerides in the 500-999 mg/dL (5.6-11.2 mmol/L) range are at risk of developing unrecognized marked increases in triglycerides, leading to pancreatitis. Patients with borderline-high serum triglyceride levels (i.e., 150 to 199 mg per dL [1.70 to 2.25 mmol per L]) and high serum triglyceride levels (i.e., 200 to 499 mg per dL [2.26 to 5.64 mmol per L]) require an overall cardiac risk assessment. Relationship to atherogenesis, Serum lipoproteins during antihypertensive therapy with beta blockers and diuretics: a controlled long-term comparative trial, Effects of alpha-adrenergic and beta-adrenergic receptor blockade on lipid metabolism, Comparison of blood pressure, plasma lipid and cardiac performance responses to prazosin versus propranolol in thiazide-treated hypertensive patients, Comparison of carvedilol and metoprolol on serum lipid concentration in diabetic hypertensive patients, Effects of antihypertensive therapy on plasma lipids and lipoproteins in the Multiple Risk Factor Intervention Trial, The effect of spironolactone on lipid, glucose and uric acid levels in blood during long-term administration to hypertensives, Novel antipsychotics and severe hyperlipidemia, Pancreatitis following Olanzapine Therapy: A Report of Three Cases. In a retrospective review of more than 250 000 patients on lipid lowering therapy, the incidence of rhabdomyolysis was 0.44 per 10 000 person years with statin monotherapy, 2.82 per 10 000 person years with fibrate monotherapy, and 5.98 per 10 000 person years with combination therapy.174 Combination of gemfibrozil with a statin was associated with a 15-fold to 20-fold higher risk of rhabdomyolysis compared with a statin-fenofibrate combination, which is therefore preferable.175 The safety and efficacy of this combination compared with either drug as monotherapy needs to be studied in patients with atherogenic dyslipidemia before it can be routinely adopted in clinical practice. She should also receive detailed instructions on diet therapy, including caloric restriction, decreasing the intake of simple sugars and saturated fat, and increasing the consumption of monounsaturated and polyunsaturated fat sources as well as dietary fiber. If hyper-triglyceridemia is a comorbidity, statins can lower triglyceride levels by 20 to 40 percent.7,11, Fibrates can markedly lower triglyceride levels (40 to 60 percent) and modestly raise HDL-C levels (15 to 25 percent).7 In patients with cardiovascular disease and moderately elevated triglyceride levels and low HDL-C levels, fibrates have been shown to decrease the risk of cardiovascular events (secondary prevention).12,13 Fibrate therapy also has been shown to decrease angiographic progression of coronary heart disease in patients with type 2 diabetes.14, Because data show decreased cardiovascular mortality rates with triglyceride reduction (more than that achieved with LDL-C reduction alone),3 there is increasing interest in fibrate use in patients with hypertriglyceridemia and in combination fibrate/statin therapy in patients with mixed dyslipidemia. They undergo hydrolysis by the lipoprotein lipase (LPL) predominantly expressed in adipose tissue and skeletal muscle, releasing free fatty acids (FFA) for these tissues and multiple remnant lipoproteins (RLP) including chylomicron remnants (CR), VLDL remnants (VLDLr), and intermediate density lipoproteins (IDL). Faergeman O. 27. : National Heart, Lung, and Blood Institute, 2002:II–7, Initial management of hypertriglyceridemia (Table 37) should include counseling for therapeutic lifestyle changes (e.g., weight control, including diet and exercise; tobacco-use cessation)7,35 and screening for metabolic syndrome. Bethesda, Md. Abdelnoor M, Relationship with etiology, onset, and severity of the disease, Dyslipidaemic pancreatitis clinical assessment and analysis of disease severity and outcomes, Acute pancreatitis in a cohort of 129 patients referred for severe hypertriglyceridemia. Adams M, et al. 2011). Harris WS, Barzi F, Stein EA, Familial hypertriglyceridemia is mostly likely caused by genetic defects combined with environmental factors. Effectiveness and tolerability of simvastatin plus fenofibrate for combined hyperlipidemia (the SAFARI trial) [Published correction appears in Am J Cardiol 2006;98:427–8]. NIH publication no. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute scientific statement [Published correction appears in Circulation 2005;112:e297]. He received his medical degree from Boston (Mass.) Patients with high serum triglyceride levels should receive counseling about a healthy diet, regular exercise, and tobacco-use cessation. The Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial was also an RCT of gemfibrozil in 2531 men with established CHD and HDL cholesterol less than 40 mg/dL and LDL cholesterol less than 140 mg/dL.165 The baseline serum triglycerides averaged about 160 mg/dL and decreased by 31% in the gemfibrozil group. 12. Contact McKenney J. et al. These are either cleared by the liver through LDL receptor related proteins (LRP) or undergo further hydrolysis by hepatic lipase (HL), leading to generation of low density lipoprotein (LDL) particles. Effect of niacin on lipid and lipoprotein levels and glycemic control in patients with diabetes and peripheral arterial disease: the ADMIT study: a randomized trial. An n-acetyl galactosamine conjugated version of this drug has been developed and shown to reduce triglyceride concentrations significantly in healthy volunteers.198 Both a monoclonal antibody (evinacumab) and an antisense oligonucleotide to ANGPTL3 have also been developed and are awaiting clinical trials. Serum triglycerides decreased by 19 mg/dL, although this was in conjunction with 2.8 kg weight loss and 2 cm decrease in waist circumference.124 The PREDIMED (Prevencion con Dieta Meditteranea) study also showed decreased prevalence of hypertriglyceridemia and metabolic syndrome in patients randomized to the Mediterranean diet supplemented by either nuts or olive oil.125, In summary, the optimal diet for patients with hypertriglyceridemia should promote weight loss, consist of not more than 50-60% carbohydrate sources comprising mostly complex carbohydrates such as whole grain and fruits and vegetables, and be rich in fiber (20-30 g/day). Initial management of hypertriglyceridemia (Table 37) should include counseling for therapeutic lifestyle changes (e.g., weight control, including diet and exercise; tobacco-use cessation)7,35 and screening for metabolic syndrome. Primary (genetic) disorders causing severe hypertriglyceridemia, *Increase in serum cholesterol may be more prominent, Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder with an estimated prevalence of one in a million. Tonstad S. Scott R, Circulation. The monoclonal antibody evinacumab and GalNac modified antisense oligonucleotide IONIS-ANGPTL3-LRx are anti-ANGPTL3 therapies, which reduce both severely elevated TGs and LDL such as in familial hypercholesterolemia. Berge KG, Pharmacological Treatment Options for Severe Hypertriglyceridemia and Familial Chylomicronemia Syndrome Expert Rev Clin Pharmacol. I. Lipid levels in 500 survivors of myocardial infarction, Linkage and association between distinct variants of the APOA1/C3/A4/A5 gene cluster and familial combined hyperlipidemia, Familial combined hyperlipidemia is associated with upstream transcription factor 1 (USF1), Pathogenesis of type III hyperlipoproteinemia (dysbetalipoproteinemia). Search terms used included hypertriglyceridemia management, hypertriglyceridemic pancreatitis, hypertriglyceridemia and cardiovascular risk, drug-induced dyslipidemia, and genetic hypertriglyceridemia. The nature of this risk largely depends on accumulation of which type of TGRL is responsible for the hypertriglyceridemia. Either intravenous insulin infusion or therapeutic plasma exchange have any benefit hypertriglyceridemia is the critical mediating. Angptl3/4 help to decrease residual risk of atherosclerotic cardiovascular disease [ Published correction appears in a review. 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